The Simbios National Center for Biomedical Computing is singularly focused on the application of physics-based simulation to problems in biology and medicine. Physics-based simulation provides a powerful framework for understanding biological form and function. Simulations are used by biologists to study macromolecular assemblies and by clinicians to analyze disease mechanisms and therapeutic options. Simulations help biomedical researchers understand the physical constraints on these systems as they engineer novel drugs, drug delivery mechanisms, synthetic tissues, medical devices, or surgical interventions. In the previous grant period, we have created a simulation toolkit (SimTK) that enables users to create and visualize accurate models and simulations of biological structures at all scales, from molecules to organisms. SimTK is an extensible, open source, freely available software package. Domain specific application software packages (built using SimTK) are distributed on our webportal, simtk.org, which has more than 8000 users and 300 software or data projects, and has enabled scientific impact in RNA biology, myosin biomechanics, protein folding, cardiovascular fluid dynamics, and neuromuscular biomechanics. SimTK applications have been developed and tested in close collaboration with biomedical scientists to ensure its utility and accuracy. In this proposal, we outline a plan to introduce three exciting new driving biological problems focusing on (1) the dynamics of neural prostheses, (2) the dynamics of cell shape, and (3) the dynamics of drug target macromolecules. We have identified the computational research challenges critical to these fields, and have assembled a strong team of researchers in modeling, simulation and visualization of biological structures that will address these challenges. The software engineering effort is lead by experienced professionals, who have previously developed and delivered complex software packages to thousands of users. Our dissemination plan includes workshops that will move online, a nationally recognized magazine, and technologies for community-based user support. Our initial efforts have established the vision, facilities, training environment, administrative organization, and collaborative relationships required for the success of Simbios. In the context of other centers focusing on complementary elements of biomedicine, our center is focused on the physical reality of biological structures. It thus provides a critical piece of a national biomedical computing infrastructure.